文章基本信息

标题：PERK-Mediated Suppression of microRNAs by Sildenafil Improves Mitochondrial Dysfunction in Heart Failure
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作者：Takashi Shimizu ; Akashi Taguchi ; Yoshiki Higashijima 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：8
页码：1-32
DOI：10.1016/j.isci.2020.101410
语种：English
出版社：Elsevier
摘要：SummaryOxidative/nitrosative stress is a major trigger of cardiac dysfunction, involving the unfolded protein response and mitochondrial dysfunction. Activation of nitric oxide-cyclic guanosine monophosphate-protein kinase G signaling by sildenafil improves cardiac mal-remodeling during pressure-overload-induced heart failure. Transcriptome analysis was conducted in failing hearts with or without sildenafil treatment. Protein kinase R–like endoplasmic reticulum (ER) kinase (PERK) downstream signaling pathways, EIF2 and NRF2, were significantly altered. Although EIF2 signaling was suppressed, NRF2 signaling was upregulated, inhibiting the maturation of miR 24-3p through EGFR-mediated Ago2 phosphorylation. To study the effect of sildenafil on these pathways, we generated cardiac-specific PERK knockout mice. In these mice, sildenafil could not inhibit the maturations, the nuclear translocation of NRF2 was suppressed, and mitochondrial dysfunction advanced. Altogether, these results show that PERK-mediated suppression of miRNAs by sildenafil is vital for maintaining mitochondrial homeostasis through NRF2-mediated oxidative stress response.Graphical AbstractDisplay OmittedHighlights•RBM3 inhibited the PERK arm of UPR in chronic heart failure (HF)•Sildenafil significantly altered PERK downstream signaling pathways, EIF2 and NRF2•PERK-mediated miRNA suppression by sildenafil was vital for mitochondrial homeostasis•Ago2 phosphorylation by EGFR was vital for inhibiting HF-induced miRNA maturationBiological Sciences; Molecular Biology; Cell Biology